Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization

Langlhofer, Georg; Janzen, Dieter; Meiselbach, Heike; Villmann, Carmen

doi:10.1016/j.neulet.2015.06.017

Cited by 8 publications

(24 citation statements)

References 21 publications

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“…Mechanism of ASICs Desensitization-The desensitization of Cys loop receptors involves rearrangements of the M2/M3 interface, which mediates the constriction of the pore and consequent reduction of ion conductance (47)(48)(49)(50)(51). We propose that ASIC desensitization entails a series of conformational rearrangements that extend from the extracellular region to the pore of the channel.…”

Section: Discussionmentioning

confidence: 99%

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

Krauson

Carattino

2016

Journal of Biological Chemistry

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Acid-sensing ion channels (ASICs) are cation-selective proton-gated channels expressed in neurons that participate in diverse physiological processes, including nociception, synaptic plasticity, learning, and memory. ASIC subunits contain intracellular N and C termini, two transmembrane domains that constitute the pore, and a large extracellular loop with defined domains termed the finger, ␤-ball, thumb, palm, and knuckle. Here we examined the contribution of the finger, ␤-ball, and thumb domains to activation and desensitization through the analysis of chimeras and the assessment of the effect of covalent modification of introduced Cys at the domain-domain interfaces. Our studies with ASIC1a-ASIC2a chimeras showed that swapping the thumb domain between subunits results in faster channel desensitization. Likewise, the covalent modification of Cys residues at selected positions in the ␤-ball-thumb interface accelerates the desensitization of the mutant channels. Studies of accessibility with thiol-reactive reagents revealed that the ␤-ball and thumb domains reside apart in the resting state but that they become closer to each other in response to extracellular acidification. We propose that the thumb domain moves upon continuous exposure to an acidic extracellular milieu, assisting with the closing of the pore during channel desensitization.Acid-sensing ion channels (ASICs) 2 are voltage-insensitive cation-permeable channels expressed in neurons of the peripheral and central nervous systems that respond to sudden changes in extracellular pH. Four genes that encode for six ASIC subunits and splice variants have been identified in mammals (ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4) (1-10). In the central nervous system, disruption of ASIC1a expression causes a number of learning and memory-related phenotypes (11)(12)(13)(14). Conversely, activation of ASIC1a has been linked to neurotoxicity in a mouse model of brain ischemia (15) and in neurodegenerative diseases such as multiple sclerosis (16), Huntington disease (17), Parkinson disease (18), and spinal cord injury (19). There is a substantial body of research that indicates that ASIC subunits participate in nociception in peripheral neurons (20 -22) as well as in pain processing in the central nervous system (23-25). Therefore, ASICs represent novel therapeutic targets to treat pain as well as neurological diseases.ASIC subunits assemble to form homo-and heterotrimers that display distinct proton sensitivities for activation and desensitization kinetics (26 -29). Although the molecular determinants for channel activation have been extensively investigated, less is known about the mechanisms that promote channel desensitization in the continual presence of protons. ASIC subunits contain two membrane-spanning helices that form the pore of the channel and connect to cytoplasmic N-and C-terminal regions and to a large extracellular loop with defined domains termed the wrist, thumb, finger, ␤-ball, knuckle, and palm (see Fig. 1) (30). In the solved structure o...

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Section: Discussionmentioning

confidence: 99%

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

Krauson

Carattino

2016

Journal of Biological Chemistry

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“…However, these data are not in good agreement with previous studies that reported that splicing of the long insert into GlyR ␣3 mRNA impacts on desensitization kinetics (12, 39 -41). Notably, desensitization of GlyR channels may be highly variable (20,41) and influenced by many parameters, such as receptor density (42), membrane potential (43), intracellular and extracellular pH (44,45), ion concentration (46,47), the membrane lipid composition, and phosphorylation of the intracellular TM3-TM4 domain or the N-glycosylation of the receptor N terminus (20). Technical features, such as slow or fast ligand application or the ligand concentration (16,48), duration of ligand administration, or the recording mode may also account for these differences.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

Raltschev

Hetsch

Winkelmann

et al. 2016

Journal of Biological Chemistry

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Glycine receptors are chloride-permeable, ligand-gated ion channels and contribute to the inhibition of neuronal firing in the central nervous system or to facilitation of neurotransmitter release if expressed at presynaptic sites. Recent structure-function studies have provided detailed insights into the mechanisms of channel gating, desensitization, and ion permeation. However, most of the work has focused only on comparing a few isoforms, and among studies, different cellular expression systems were used. Here, we performed a series of experiments using recombinantly expressed homomeric and heteromeric glycine receptor channels, including their splice variants, in the same cellular expression system to investigate and compare their electrophysiological properties. Our data show that the current-voltage relationships of homomeric channels formed by the ␣2 or ␣3 subunits change upon receptor desensitization from a linear to an inwardly rectifying shape, in contrast to their heteromeric counterparts. The results demonstrate that inward rectification depends on a single amino acid (Ala 254 ) at the inner pore mouth of the channels and is closely linked to chloride permeation. We also show that the current-voltage relationships of glycine-evoked currents in primary hippocampal neurons are inwardly rectifying upon desensitization. Thus, the alanine residue Ala 254 determines voltage-dependent rectification upon receptor desensitization and reveals a physio-molecular signature of homomeric glycine receptor channels, which provides unprecedented opportunities for the identification of these channels at the single cell level.

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“…1, A and B). Unfortunately, to facilitate crystallization of these proteins, the large intracellular domain that connects TM3 and TM4 was truncated or replaced by short peptide linkers, so it is currently not experimentally resolved (Thompson et al, 2010;Langlhofer et al, 2015).…”

Section: General Structure Of Cys-loop Receptorsmentioning

confidence: 99%

Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors

2016

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Glycine receptors (GlyR) are inhibitory Cys-loop ion channels that contribute to the control of excitability along the central nervous system (CNS). GlyR are found in the spinal cord and brain stem, and more recently they were reported in higher regions of the CNS such as the hippocampus and nucleus accumbens. GlyR are involved in motor coordination, respiratory rhythms, pain transmission, and sensory processing, and they are targets for relevant physiologic and pharmacologic modulators. Several studies with protein crystallography and cryoelectron microscopy have shed light on the residues and mechanisms associated with the activation, blockade, and regulation of pentameric Cys-loop ion channels at the atomic level. Initial studies conducted on the extracellular domain of acetylcholine receptors, ion channels from prokaryote homologs-Erwinia chrysanthemi ligand-gated ion channel (ELIC), Gloeobacter violaceus ligand-gated ion channel (GLIC)-and crystallized eukaryotic receptors made it possible to define the overall structure and topology of the Cys-loop receptors. For example, the determination of pentameric GlyR structures bound to glycine and strychnine have contributed to visualizing the structural changes implicated in the transition between the open and closed states of the Cys-loop receptors. In this review, we summarize how the new information obtained in functional, mutagenesis, and structural studies have contributed to a better understanding of the function and regulation of GlyR.

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Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization

Cited by 8 publications

References 21 publications

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

The Thumb Domain Mediates Acid-sensing Ion Channel Desensitization

Electrophysiological Signature of Homomeric and Heteromeric Glycine Receptor Channels

Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors

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